CA2632272A1 - Sulfamoyl sulfonate prodrugs - Google Patents
Sulfamoyl sulfonate prodrugs Download PDFInfo
- Publication number
- CA2632272A1 CA2632272A1 CA002632272A CA2632272A CA2632272A1 CA 2632272 A1 CA2632272 A1 CA 2632272A1 CA 002632272 A CA002632272 A CA 002632272A CA 2632272 A CA2632272 A CA 2632272A CA 2632272 A1 CA2632272 A1 CA 2632272A1
- Authority
- CA
- Canada
- Prior art keywords
- quinine
- sulphamoylphenylsulphonate
- beta
- trien
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000651 prodrug Substances 0.000 title claims abstract description 23
- 229940002612 prodrug Drugs 0.000 title claims abstract description 23
- UYSRSLSTXYYNEW-UHFFFAOYSA-N NS(=O)(=O)S(O)(=O)=O Chemical compound NS(=O)(=O)S(O)(=O)=O UYSRSLSTXYYNEW-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 24
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- -1 hydroxyl- Chemical group 0.000 claims description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 210000003743 erythrocyte Anatomy 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 7
- 238000011321 prophylaxis Methods 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229960000948 quinine Drugs 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 239000003430 antimalarial agent Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000002777 nucleoside Substances 0.000 claims description 5
- 229960005179 primaquine Drugs 0.000 claims description 5
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 claims description 5
- 239000000583 progesterone congener Substances 0.000 claims description 5
- 150000003431 steroids Chemical class 0.000 claims description 5
- 235000000346 sugar Nutrition 0.000 claims description 5
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 5
- 229960002555 zidovudine Drugs 0.000 claims description 5
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims description 4
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 claims description 4
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 claims description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003098 androgen Substances 0.000 claims description 4
- 229960003473 androstanolone Drugs 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 4
- 229960003309 dienogest Drugs 0.000 claims description 4
- AZFLJNIPTRTECV-FUMNGEBKSA-N dienogest Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)([C@](CC3)(O)CC#N)CC3)C3=C21 AZFLJNIPTRTECV-FUMNGEBKSA-N 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000000262 estrogen Substances 0.000 claims description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 4
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004171 hydroxychloroquine Drugs 0.000 claims description 4
- 229930013032 isoflavonoid Natural products 0.000 claims description 4
- 150000003817 isoflavonoid derivatives Chemical class 0.000 claims description 4
- 235000012891 isoflavonoids Nutrition 0.000 claims description 4
- 229960004400 levonorgestrel Drugs 0.000 claims description 4
- 229960001962 mefloquine Drugs 0.000 claims description 4
- 229940053934 norethindrone Drugs 0.000 claims description 4
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims description 4
- 125000003835 nucleoside group Chemical group 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- 229960003604 testosterone Drugs 0.000 claims description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 4
- YSGQGNQWBLYHPE-UHFFFAOYSA-N 17-hydroxy-7,13-dimethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2(C)C(O)CCC2C2C(C)CC3=CC(=O)CCC3C21 YSGQGNQWBLYHPE-UHFFFAOYSA-N 0.000 claims description 3
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910005948 SO2Cl Inorganic materials 0.000 claims description 3
- 239000003418 antiprogestin Substances 0.000 claims description 3
- 125000000732 arylene group Chemical group 0.000 claims description 3
- 229960001169 brivudine Drugs 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 claims description 3
- 229960001936 indinavir Drugs 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 229960004719 nandrolone Drugs 0.000 claims description 3
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 claims description 3
- 229960000884 nelfinavir Drugs 0.000 claims description 3
- 239000002379 progesterone receptor modulator Substances 0.000 claims description 3
- 230000003637 steroidlike Effects 0.000 claims description 3
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 claims description 2
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 claims description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 2
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 claims description 2
- 229930024421 Adenine Natural products 0.000 claims description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- 201000009273 Endometriosis Diseases 0.000 claims description 2
- 206010058359 Hypogonadism Diseases 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- 229960000643 adenine Drugs 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- 229940030486 androgens Drugs 0.000 claims description 2
- GJMNAFGEUJBOCE-MEQIQULJSA-N asoprisnil Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@]([C@]3(C2)C)(COC)OC)=CC=C(\C=N\O)C=C1 GJMNAFGEUJBOCE-MEQIQULJSA-N 0.000 claims description 2
- 229950003620 asoprisnil Drugs 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 229940104302 cytosine Drugs 0.000 claims description 2
- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 claims description 2
- 229960004845 drospirenone Drugs 0.000 claims description 2
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 229930182833 estradiol Natural products 0.000 claims description 2
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 claims description 2
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 claims description 2
- 238000002657 hormone replacement therapy Methods 0.000 claims description 2
- 229960000890 hydrocortisone Drugs 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 229960003248 mifepristone Drugs 0.000 claims description 2
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 claims description 2
- 229950011093 onapristone Drugs 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229940095745 sex hormone and modulator of the genital system progesterone receptor modulator Drugs 0.000 claims description 2
- 229940113082 thymine Drugs 0.000 claims description 2
- 229940035893 uracil Drugs 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims 4
- NNKXWRRDHYTHFP-HZQSTTLBSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;hydron;dichloride Chemical compound Cl.Cl.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 NNKXWRRDHYTHFP-HZQSTTLBSA-N 0.000 claims 2
- QTQWMSOQOSJFBV-UHFFFAOYSA-N pamaquine Chemical compound C1=CN=C2C(NC(C)CCCN(CC)CC)=CC(OC)=CC2=C1 QTQWMSOQOSJFBV-UHFFFAOYSA-N 0.000 claims 2
- 229950000466 pamaquine Drugs 0.000 claims 2
- 239000001096 (4-ethenyl-1-azabicyclo[2.2.2]octan-7-yl)-(6-methoxyquinolin-4-yl)methanol hydrochloride Substances 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims 1
- XHKUDCCTVQUHJQ-BILMMMPYSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 XHKUDCCTVQUHJQ-BILMMMPYSA-N 0.000 claims 1
- MAYUSTFJKJSJNC-DSXUQNDKSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1O.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 MAYUSTFJKJSJNC-DSXUQNDKSA-N 0.000 claims 1
- GKRXTXTYZVRRAI-HZQSTTLBSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;dihydrobromide Chemical compound Br.Br.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 GKRXTXTYZVRRAI-HZQSTTLBSA-N 0.000 claims 1
- LKUVXQMSYPYURB-DSXUQNDKSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;formic acid Chemical compound OC=O.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LKUVXQMSYPYURB-DSXUQNDKSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 201000009030 Carcinoma Diseases 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- NSBRKSWSLRQPJW-WWLNLUSPSA-N [(r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methyl] ethyl carbonate Chemical compound C1=C(OC)C=C2C([C@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)OC(=O)OCC)=CC=NC2=C1 NSBRKSWSLRQPJW-WWLNLUSPSA-N 0.000 claims 1
- 229960000981 artemether Drugs 0.000 claims 1
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 claims 1
- 229960002970 artemotil Drugs 0.000 claims 1
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 claims 1
- 229960004991 artesunate Drugs 0.000 claims 1
- 201000008275 breast carcinoma Diseases 0.000 claims 1
- 229960003677 chloroquine Drugs 0.000 claims 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 claims 1
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 claims 1
- 230000035558 fertility Effects 0.000 claims 1
- 229940045109 genistein Drugs 0.000 claims 1
- 235000006539 genistein Nutrition 0.000 claims 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000002207 metabolite Substances 0.000 claims 1
- 230000003071 parasitic effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000000843 phenylene group Chemical class C1(=C(C=CC=C1)*)* 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 claims 1
- 229960005385 proguanil Drugs 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 125000005551 pyridylene group Chemical class 0.000 claims 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 claims 1
- 229960000611 pyrimethamine Drugs 0.000 claims 1
- 229960002522 quinine dihydrochloride Drugs 0.000 claims 1
- 229960001811 quinine hydrochloride Drugs 0.000 claims 1
- 229960002991 quinine salicylate Drugs 0.000 claims 1
- ZHNFLHYOFXQIOW-LPYZJUEESA-N quinine sulfate dihydrate Chemical compound [H+].[H+].O.O.[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-LPYZJUEESA-N 0.000 claims 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 210000000936 intestine Anatomy 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- ALIQZUMMPOYCIS-UHFFFAOYSA-N benzene-1,3-disulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC(S(Cl)(=O)=O)=C1 ALIQZUMMPOYCIS-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 210000004051 gastric juice Anatomy 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ASLVVDVJYDCLPC-UHFFFAOYSA-N 2-sulfamoylbenzenesulfonic acid Chemical compound NS(=O)(=O)C1=CC=CC=C1S(O)(=O)=O ASLVVDVJYDCLPC-UHFFFAOYSA-N 0.000 description 3
- 108090000371 Esterases Proteins 0.000 description 3
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 3
- 229960000571 acetazolamide Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 125000002560 nitrile group Chemical group 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 150000003871 sulfonates Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YSGQGNQWBLYHPE-CFUSNLFHSA-N (7r,8r,9s,10r,13s,14s,17s)-17-hydroxy-7,13-dimethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 YSGQGNQWBLYHPE-CFUSNLFHSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 101000984236 Homo sapiens Carbonic anhydrase 1 Proteins 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- YXYXCSOJKUAPJI-ZBRFXRBCSA-N [(8r,9s,13s,14s,17s)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] sulfamate Chemical group NS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 YXYXCSOJKUAPJI-ZBRFXRBCSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000012062 aqueous buffer Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000004848 nephelometry Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- MRCKRGSNLOHYRA-UHFFFAOYSA-N (2-nitrophenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1[N+]([O-])=O MRCKRGSNLOHYRA-UHFFFAOYSA-N 0.000 description 1
- XOGODJOZAUTXDH-UHFFFAOYSA-M (N-methylanilino)methanesulfonate Chemical compound CN(CS([O-])(=O)=O)c1ccccc1 XOGODJOZAUTXDH-UHFFFAOYSA-M 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- PWSQDFHPBVRXTQ-UHFFFAOYSA-N 3-sulfamoylbenzenesulfonyl chloride Chemical compound NS(=O)(=O)C1=CC=CC(S(Cl)(=O)=O)=C1 PWSQDFHPBVRXTQ-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102100024633 Carbonic anhydrase 2 Human genes 0.000 description 1
- 101710167917 Carbonic anhydrase 2 Proteins 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000760643 Homo sapiens Carbonic anhydrase 2 Proteins 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical group C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 150000001885 cortisol derivatives Chemical class 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- SLRCCWJSBJZJBV-BYNSBNAKSA-N genisteine Chemical compound C1N2CCCC[C@@H]2[C@@H]2CN3CCCC[C@@H]3[C@H]1C2 SLRCCWJSBJZJBV-BYNSBNAKSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention relates to the sulfamoyl sulfonate prodrugs of general formula (I), to a method for producing them, to pharmaceutical compositions containing the same and to their use for producing orally available drugs. The compounds according to the invention bind to carboanhydrases and inhibit these enzymes.
Description
Sulfamoyl Sulfonate Prodrugs The invention relates to sulfamoyl sulfonate prodrugs of general formula I, //O
X ~=0 js~ NH 2 p ~\
O
Drug ; Gruppe Z
[Group Z] (I), a process for the production of these prodrugs, pharmaceutical compositions that contain these compounds, and their use for the production of orally available pharmaceutical agents.
From WO 01/91797, steroidal compounds that are bonded via an -S02NR1R2 group to erythrocytes and that accumulate there are known. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000:1, preferably 30-1000:1, so that a depot formation in the erythrocytes can be mentioned. Because of the strong binding of the compounds to the erythrocytes, metabolization is avoided during passage through the liver.
Disadvantageously, no therapy-relevant active ingredient levels are given despite a reduced metabolization with the indicated dosages. Reasons for this can be sought in excessive binding to erythrocytes, an enzyme-induced cleavage and in low solubilities.
It is the object of the invention to provide new prodrugs that are orally available and that, in comparison to the prior art, ensure a therapy-relevant active ingredient level even at a low dosage.
This object is achieved by sulfamoyl sulfonate prodrugs of general formula (I), in which a sulfamoyl radical is bonded to the drug that is to be released via a spacer X by means of a sulfonate bond.
X ~=0 js~ NH 2 p ~\
O
Drug ; Gruppe Z
[Group Z] (I), a process for the production of these prodrugs, pharmaceutical compositions that contain these compounds, and their use for the production of orally available pharmaceutical agents.
From WO 01/91797, steroidal compounds that are bonded via an -S02NR1R2 group to erythrocytes and that accumulate there are known. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000:1, preferably 30-1000:1, so that a depot formation in the erythrocytes can be mentioned. Because of the strong binding of the compounds to the erythrocytes, metabolization is avoided during passage through the liver.
Disadvantageously, no therapy-relevant active ingredient levels are given despite a reduced metabolization with the indicated dosages. Reasons for this can be sought in excessive binding to erythrocytes, an enzyme-induced cleavage and in low solubilities.
It is the object of the invention to provide new prodrugs that are orally available and that, in comparison to the prior art, ensure a therapy-relevant active ingredient level even at a low dosage.
This object is achieved by sulfamoyl sulfonate prodrugs of general formula (I), in which a sulfamoyl radical is bonded to the drug that is to be released via a spacer X by means of a sulfonate bond.
Sulfamoyl sulfonate prodrugs of general formula (I) are X S=0 S NHZ
p~ \0 Drug Gruppe Z
[Group Z] (I), in which X is a C1_12-alkanediyl-, a CPFZp group where p= 1-5, a C3_g-cycloalkanediyl-, an arylene-, a heteroalkanediyl-, a C1.4-alkanediylaryl-, a C1_4-alkanediyl-C3_8-cycloalkyl- or a C3_8-cycloalkanediyl-C1_4-alkyl group, and Drug is a pharmaceutical active ingredient that can form a sulfonate via an OH
group, such as steroids, anti-malaria agents, nucleosides, or isoflavonoids, which can optionally be substituted.
The sulfamoyl sulfonate compounds according to the invention bond to erythrocytes, are readily water-soluble and are hydrolytically cleaved without assistance from enzymes.
For the purpose of this invention, "C1_12-alkanediyl group" is defined as a double-bonded, branched or straight-chain alkylene radical with up to 12 carbon atoms that optionally can be substituted with, e.g., halogen atoms, hydroxy groups, or nitrile groups. As examples, a methane-l,l-diyl-, ethane-1,2-diyl, propane-1,3-diyl-, butane-l,4-diyl-, pentane-1,5-diyl-; hexane-1,6-diyl-, octane-l,8-diyl-, and undecane-1,11-diyl group can be mentioned.
For the purpose of this invention, CPF2P group with p = 1-5 is defined as a branched or straight-chain perfluorinated alkyl radical with up to 5 carbon atoms. As examples, a perfluoropropane-1,3-diyl-, perfluorobutane-1,4-diyl-, and perfluoropentarie-1,5-diyl group can be mentioned.
The above-mentioned "C3_8-cycloalkanediyl group" means, according to the invention, a double-bonded, mono- or bicyclic, carbocyclic group with 3 to 8 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, and nitrile groups, such as, for example, with a cyclobutane-1,3-diyl-, cyclopentane-1,3-diyl- or a cyclohexane-1,4-diyl group.
The above-mentioned "arylene group" means, according to the invention, a double-bonded, aromatic mono- to tricyclic, carbocyclic group with 6 to 15 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, nitrile groups, and alkyl groups, such as, for example, with an m-phenylene-, p-phenylene-, phenanthrylene- or a naphthalene group.
The heteroarylene radical includes, in each case, 5-16 ring atoms and contains, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, in the ring. The heteroaryl radical can be mono-, bi- or tricyclic.
For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, benzothiazole, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, and isoquinolyl.
For the purpose of the invention, a heteroalkanediyl group is a double-bonded, straight-chain or branched, saturated or unsaturated heteroalkyl radical with, in each case, 1-6 carbon atoms and can contain, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, such as, for example, a bis-ethylenoxy radical.
p~ \0 Drug Gruppe Z
[Group Z] (I), in which X is a C1_12-alkanediyl-, a CPFZp group where p= 1-5, a C3_g-cycloalkanediyl-, an arylene-, a heteroalkanediyl-, a C1.4-alkanediylaryl-, a C1_4-alkanediyl-C3_8-cycloalkyl- or a C3_8-cycloalkanediyl-C1_4-alkyl group, and Drug is a pharmaceutical active ingredient that can form a sulfonate via an OH
group, such as steroids, anti-malaria agents, nucleosides, or isoflavonoids, which can optionally be substituted.
The sulfamoyl sulfonate compounds according to the invention bond to erythrocytes, are readily water-soluble and are hydrolytically cleaved without assistance from enzymes.
For the purpose of this invention, "C1_12-alkanediyl group" is defined as a double-bonded, branched or straight-chain alkylene radical with up to 12 carbon atoms that optionally can be substituted with, e.g., halogen atoms, hydroxy groups, or nitrile groups. As examples, a methane-l,l-diyl-, ethane-1,2-diyl, propane-1,3-diyl-, butane-l,4-diyl-, pentane-1,5-diyl-; hexane-1,6-diyl-, octane-l,8-diyl-, and undecane-1,11-diyl group can be mentioned.
For the purpose of this invention, CPF2P group with p = 1-5 is defined as a branched or straight-chain perfluorinated alkyl radical with up to 5 carbon atoms. As examples, a perfluoropropane-1,3-diyl-, perfluorobutane-1,4-diyl-, and perfluoropentarie-1,5-diyl group can be mentioned.
The above-mentioned "C3_8-cycloalkanediyl group" means, according to the invention, a double-bonded, mono- or bicyclic, carbocyclic group with 3 to 8 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, and nitrile groups, such as, for example, with a cyclobutane-1,3-diyl-, cyclopentane-1,3-diyl- or a cyclohexane-1,4-diyl group.
The above-mentioned "arylene group" means, according to the invention, a double-bonded, aromatic mono- to tricyclic, carbocyclic group with 6 to 15 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, nitrile groups, and alkyl groups, such as, for example, with an m-phenylene-, p-phenylene-, phenanthrylene- or a naphthalene group.
The heteroarylene radical includes, in each case, 5-16 ring atoms and contains, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, in the ring. The heteroaryl radical can be mono-, bi- or tricyclic.
For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, benzothiazole, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, and isoquinolyl.
For the purpose of the invention, a heteroalkanediyl group is a double-bonded, straight-chain or branched, saturated or unsaturated heteroalkyl radical with, in each case, 1-6 carbon atoms and can contain, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, such as, for example, a bis-ethylenoxy radical.
The "C14-arylalkanediyl group" is an aryl group that is bonded to a skeleton via a C1 C4-alkanediyl group, whereby the alkanediyl group can be straight-chain or branched. For example, benzyl or phenethylene can be mentioned.
The "C3_8-cycloalkyl-C1_4-alkanediyl group" means, for example, cycloalkyl-(CH2)-, cycloalkyl-(C2H4)-, cycloalkyl-(C3H6)-, cycloalkyl-(C4Hg)-, or cycloalkyl-(C5H,o)-. In this case, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
"C1_4-Alkyl-C3_8-cycloalkanediyl group" is defined as methylcycloalkanediyl, ethyl-cycloalkanediyl, propylcycloalkanediyl, butylcycloalkanediyl, or pentylcycloalkanediyl. In this case, cycloalkanediyl can be cyclopropane-1,3-diyl, cyclobutane-1,4-diyl, cyclopentane-1,5-diyl, cyclohexane-1,6-diyl, cycloheptane-1,7-diyl or cyclooctane-1,8-diyl.
In the context of this invention, the term "halogen atom" is defined as a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, or bromine atom.
A pharmaceutical active ingredient that can form a sulfonate via an OH group means, for the purpose of the invention, the following:
Steroids: Estrogens, for example estradiol or estriol, or androgens, for example testosterone, MENT (7 a-methyl-19-nortestosterone), eF-MENT (11 -fluoro-7 a-methyl-l9-nortestosterone), nandrolone, DHT (dihydrotestosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol Anti-malaria agents: quinine, cinchonidine, hydroxychloroquine, primaquine, mefloquine;
or Nucleosides: consisting of a sugar, such as ribose or deoxyribose, and a base, such as adenine, guanine, cytosine, thymine or uracil, and also zidovudine, brivudine, indinavir, and nelfinavir;
Isoflavonoids: genisteine.
Especially preferred compounds are specified as follows:
1) 3-hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate, 2) 3-acetoxyestra-1,3,5(10)-trien-17(3-yl 3'- sulfamoylphenyl sulfonate, 3) 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 4) 3-hydroxyestra-1,3,5(10)-trien-l7R-y14'-sulfamoylphenyl sulfonate, 5) 2-methoxy-3-hydroxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 6) 3,16a-dihydroxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate, 7) 3,170 -dihydroxyestra-1,3,5(10)-trien-16a-y13'-sulfamoylphenyl sulfonate, 8) 3-benzoyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 9) quinine-3'-sulfamoylphenyl sulfonate, 10) cinchonidine-3'-sulfamoylphenyl sulfonate, 11) zidovudine-3'-sulfamoylphenyl sulfonate, 12) 3-oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 13) 3-oxoandrostan-17P-yl 3'-sulfamoylphenyl sulfonate, 14) 3-oxo-7a-methylandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 15) 3-oxoestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate, and 16) brivudine-3'-sulfamoylphenyl sulfonate.
The therapeutically relevant drug compound is released through hydrolysis from the compounds according to the invention.
In-Vitro Tests:
Carbonic Anhydrase Inhibition Test Principle:
Photometric determination of the inhibition of human carbonic anhydrase I or II with sulfonamides or sulfamates on microtiter plates with the aid of enzymatic conversion of nitrophenyl acetate with a color change from colorless to yellow.
Table 1: IC50 Inhibiting Values of Human Carbonic Anhydrase I
CAII CAI
Inhibitor IC50 (nM) IC50 (nM) Estradiol-3-sulfamat 34 157 10.6 3-Oxoandrost-4-en-17R-yI 120 2300 3'-aminosulfonylphenyl-sulfonat 3-Oxo-7a-methylandrost-4- 120 2300 en-170-yi 3'-aminosulfonyl-hen Isulfonat 3-Hydroxyestra-1,3,5(10)- 81 1700 trien-17p-yl 3'-aminosulfo-n I hen Isulfonat Zidovudinsulfonat 1100 2900 Acetazolamid 61 1200 bekannter CA-Hemmer) 190 Literature: 1) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).
[Key to Table 1:]
Estradiol-3-sulfamat = Estradiol-3-sulfamate 3-Oxoandrost-4-en-17R-yl 3'-aminosulfamoylphenylsulfonat = 3-Oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate 3 -Oxo-7a-methylandrost-4-en-17 0-yl 3'-aminosulfamoylphenylsulfonat = 3 -Oxo-7a-methylandrost-4-en-17(3-yl 3'-aminosulfamoylphenyl sulfonate 3-Hydroxyestra-1,3,5(10)-trien-17(3-yl 3'-aminosulfonylphenylsulfonat = 3-Hydroxyestra-1,3,5(10)-trien-l7R-yl 3'-aminosulfonylphenyl sulfonate Zidovudinsulfonat = Zidovudine Sulfonate Acetazolamid (bekannter CA-Hemmer) = Acetazolamide (Known CA Inhibitor) It was found that the sulfamoyl sulfonate prodrugs according to the invention surprisingly readily inhibit the carbonic anhydrase II. A concentration of the prodrugs, according to the invention, in the erythrocytes can be deduced from this.
Physicochemical Data Solubility in Water a) Kinetic Measurement:
The compounds according to the invention were measured as 10 mmol DMSO
solution in a 0.01 M phosphate buffer solution at pH 7.4 and 25 C with nephelometry and turbidity.
While in a turbid state, the solution to be tested was added drop by drop to the buffer solution until a precipitate settled.
The precipitate was detected in a dilution series (compounds in a phosphate buffer solution according to the invention) by nephelometry.
b.) Thermodynamic Measurement:
The compounds in solid form according to the invention were added to an excess of an aqueous buffer system of various pH values. It was stirred 24 hours at 25 C. After centrifuging, the solution was examined with HPLC (HPLC: column: Xterra MS C18 2.5 m, 30 x 4.6 mm). Two standard gradient systems were used based on the compounds to be measured:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B.
Table 2: Water Solubility Substance Solubility in Water Estradiol-3-sulfamate 0.15 mg/100 ml Testosterone Propionate Insoluble 3-Hydroxyestra-1,3,5(10)-trien-170-y13'- 3 mg/1 sulfamoylphenyl Sulfonate 3-Oxoandrost-4-en-170-yl 3'-sulfamoyl- 5 mg/l phenyl Sulfonate 3-Oxo-7a-methylandrost-4-en-17(3-yl 3'- About 6 mg/1 sulfamoylphenyl Sulfonate The compounds according to the invention show a higher solubility when compared to sulfamate- and carboxylic acid ester prodrugs, which allows for better absorption in the intestine.
Hydrolysis The compounds according to the invention were measured as a DMSO solution in an aqueous buffer of various pH values at 37 C.
The quantification took place through HPLC (HPLC column: Xterra MS C18 2.5 m 4.6 x 30mm). Based on the test substances to be measured, the following gradient system was used for the HPLC:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3=5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B. The quantification took' place after 1 and 2 hours and after 24 hours.
Stability in Simulated Gastric Juice:
Solutions of the compounds according to the invention were incubated at 37 C
in simulated gastric juice (aqueous NaCI solution with pepsin, pH- 1.2).
The quantification took place through HPLC (HPLC-column: Xterra MS C18 2.5 m 4.6 x 30mm) using the gradient system:
A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0.01 % trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B.
The quantification took place after 0.5, 1, 1.5 and 2 hours.
Table 3: Hydrolysis/Stability in Gastric Juice Decomposition in %
pH =1, 37 C pH = 7.4, 37 C
Substance 30 min 1 h 2 h 24 h 1 h 2h. 24 h 3-Hydroxyestra-1,3,5 4 7 14 80 6 13 84 (10)-trien-17(3-yl3'- (pH=1.2) sulfamoyl-phenyl sulfonate 3-Oxoandrost-4-en- 3 6 11 78 6 12 75 17 (3-y13'-sulfamoyl- (pH=1.2) phenyl sulfonate 3-Oxo-7a-methyl- 6 11 71 6 11 70 androst-4-en-17p-yl 3'-sulfamoylphenyl sulfonate 3-Oxoandrost-4-en- 0 0 0 0 0 0 0 17(3-yl n-propionate Carboxylic acid esters are relatively stable in gastric juice (pH - 1) and in the intestine (pH - 7.4), but are cleaved when passing through the intestine by esterases that exist there. During passage through the stomach, however, the stable prodrug remains almost complete.
The cleavage of the carboxylic acid ester thus takes place when passing through the intestine and in the liver.
No enzymes (esterases) are known for sulfonic acid ester. It was therefore surprising that the sulfonates are still cleaved, whereby a simple hydrolysis takes place. Although a slow hydrolysis already takes place in the gastric juice and when the pH = 7.4, the sulfonates have adequate stability to pass through the stomach and the intestine. An esterase cleavage does not take place in the intestine wall. The first-pass effect in the liver is avoided since the sulfonates are bonded with the sulfonamide group to the erythrocytes.
The compounds of general formula (I) according to the invention can, as a function of the meaning of "drug," be used for the treatment and/or prophylaxis of various clinical pictures. For example, the compounds of general formula (I) can be used if the "drug" is a steroid, such as androgen or estrogen, in hormone replacement therapy (HRT) in women and men, or in the treatment of hormonally-induced diseases in men (prostrate cancer, breast cancer, hypogonadism) and in women (endometriosis, breast cancer). In addition, the compounds of general formula (I) according to the invention, in which "drug,"
for example, stands for an androgen or estrogen, can he used for birth control in men and women.
The use of additional active ingredients mentioned for "drug," such as quinine, cinchonidine, hydroxychloroquine, primaquine or mefloquine, relates to the treatment of malaria.
Compounds of general formula (I) according to the invention, in which "drug"
means a cortisol derivative, can be used for the treatment and prophylaxis of inflammatory and/or allergic diseases that are influenced by immunosuppressive agents and/or antiproliferative agents.
Prodrugs according to the invention, in which "drug" means a nucleoside (zidovudine, brivudine, indinavir, nelfinavir), can be used for the treatment of viral diseases (herpes, HIV).
In addition, subjects of the invention are the pharmaceutical compositions that contain the compounds of general formula (I) according to the invention and optionally additional active ingredients, for example gestagens (norethisterone, dienogest, drospirenone, levonorgestrel), antigestagens (mifepristone, onapristone) and/or progesterone receptor modulators (mesoprogestins, such as asoprisnil).
These pharmaceutical compositions and pharmaceutical agents are preferably administered orally. In addition to the usual vehicles and/or diluents, they contain at least one compound of general formula I.
Dosage The prodrugs according to the invention can be administered orally.
Generally, satisfactory results are to be expected both for the treatment and/or prophylaxis of the above-mentioned indications or for birth control if the dosage is carried out in such a way that after the administration of the prodrugs, an amount of the corresponding active ingredient ("drug") is released that corresponds to the highest pharmaceutically used maximum dose of the respective "drug" substance.
The pharmaceutical agents of the invention are produced in a known way with the usual solid or liquid vehicles or diluents and the commonly used pharmaceutical-technical adjuvants corresponding to the desired form of administration with a suitable dosage. The preferred preparations are in a dispensing form that is suitable for oral administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.
Corresponding tablets can be obtained by, for example, mixing the active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxylpolymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tablets can accordingly be produced by coating cores, which are produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the shells for the coated tablets can also consist of several layers, whereby the adjuvants mentioned above with the tablets can be used.
Solutions or suspensions with the compounds of general formula I according to the invention can contain additional taste-improving agents such as saccharin, cyclamate or sugar, as well as, e.g., flavoring substances such as vanilla or orange extract. In addition, they can contain suspending adjuvants such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoate.
The capsules that contain compounds of general formula I can be produced by, for example, the compound(s) of general formula (I) being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.
The prodrugs according to the invention can be synthesized according to the following examples, whereby the latter are used for a more detailed explanation without limiting the invention.
General Synthesis Instructions Variant 1 Reaction with Disulfonic Acid Chlorides A disulfonic acid chloride of general formula S02-X-SO2Cl is dissolved under a cover gas in a base, such as, e.g., pyridine. The corresponding amount of a drug substance is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, the reaction mixture is stirred into a concentrated NH3 solution. The precipitate is filtered off, washed with water and dried. The residue is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel.
Corresponding sulfamoyl sulfonates are obtained.
Variant 2 Reaction with Sulfamoyl Sulfonic Acid Halides A drug substance, as defined above, is dissolved under a cover gas in a base, such as, e.g., pyridine, and an inert solvent, such as, e.g., chloroform. While being cooled, the corresponding amount of a sulfamoyl sulfonic acid halide of general formula SO2Hal is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, water is added, and it is optionally acidified with an acid, such as, e.g., 10%
HCI. It is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant, such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel. Corresponding sulfamoyl sulfonates are obtained.
The corresponding sulfamoyl sulfonic acid halides or disulfonic acid chlorides are commercially available or can be produced by methods that are known to one skilled in the art.
Synthesis Examples Example 1 3 -tert-Butyldimethylsilyloxyestra-1 3 5(10)-trien-17(i-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of 3-tert=butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-ol is added. After 2 hours, the reaction mixture is stirred into 25 ml of a concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-tert-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.14 (s, 6 H, SiMe), 0.77 (s, 3 H, 18-Me), 0.93 (s, 9 H, t.-Bu), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NHZ).
Example 2 3 -Hydroxyestra-1 3 5(10)-trien-l7R-yl 3'-sulfamoylphenyl Sulfonate 300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is dissolved in 20 ml of THF. While being stirred, 200 mg of tetrabutyl ammonium fluoride is added at room temperature. After 1 hour, 20 ml of water is stirred in. The substance is extracted with ethyl acetate. The organic phase is washed with saturated NaCI solution, dried on MgSOa, filtered, concentrated by evaporation and chromatographed on silica gel. 3-Hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-d6): 0.76 (s, 3 H, 18-Me), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NH2), 8.98 (s, 1H, 3-OH).
Example 3 3 -Oxo-7a-methylestra-4-en-17 D-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of MENT is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes; it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-7a-methylestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.66 (d, 3 H, 7-Me), 4.38 (t, 1 H, 17-H), 5.69 (s; 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 4 3-Oxo-androst-4-en-17p-yl 3'-sulfamoylphenyl Sulfonate Variant 1 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine.
Then, 1.0 g of testosterone is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17R-y13'-sulfamoylphenyl sulfonate is obtained.
Variant 2 1.0 g of testosterone is dissolved under argon in 5.5 ml of pyridine. Then, 1.8 g of 3-aminosulfonylphenylsulfonyl chloride is added. After 2 hours, the reaction mixture is stirred into 25 ml of water and acidified with 10% HCI. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
1H-N1VIR (DMSO-D6): 0.78 (s, 3 H, 18-Me), 1.11 (s, 3 H, 19-Me), 4.34 (t, 1 H, H), 5.60 (s, 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 5 Zidovudine-sulfamoylphenyl Sulfonate 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine..
Then, 1.0 g of zidovudine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation and the residue is chromatographically purified on silica gel.
Zidovudine-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-D6): 1.17 (s, 3 H, Me), 2.40 (m, 2 H, CH2), 4.00 (m, 1 H, CH), 4.42 (m, 2 H, CH2), 6.09 (m, 1 H, CH), 7.40 (s, 1 H, CH), 7.66 (s, 2 H, NH2), 7.85-8.30 (3 m + s, 5 H, 4-H), 11.35 (s, 1 H, NH).
The "C3_8-cycloalkyl-C1_4-alkanediyl group" means, for example, cycloalkyl-(CH2)-, cycloalkyl-(C2H4)-, cycloalkyl-(C3H6)-, cycloalkyl-(C4Hg)-, or cycloalkyl-(C5H,o)-. In this case, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
"C1_4-Alkyl-C3_8-cycloalkanediyl group" is defined as methylcycloalkanediyl, ethyl-cycloalkanediyl, propylcycloalkanediyl, butylcycloalkanediyl, or pentylcycloalkanediyl. In this case, cycloalkanediyl can be cyclopropane-1,3-diyl, cyclobutane-1,4-diyl, cyclopentane-1,5-diyl, cyclohexane-1,6-diyl, cycloheptane-1,7-diyl or cyclooctane-1,8-diyl.
In the context of this invention, the term "halogen atom" is defined as a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, or bromine atom.
A pharmaceutical active ingredient that can form a sulfonate via an OH group means, for the purpose of the invention, the following:
Steroids: Estrogens, for example estradiol or estriol, or androgens, for example testosterone, MENT (7 a-methyl-19-nortestosterone), eF-MENT (11 -fluoro-7 a-methyl-l9-nortestosterone), nandrolone, DHT (dihydrotestosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol Anti-malaria agents: quinine, cinchonidine, hydroxychloroquine, primaquine, mefloquine;
or Nucleosides: consisting of a sugar, such as ribose or deoxyribose, and a base, such as adenine, guanine, cytosine, thymine or uracil, and also zidovudine, brivudine, indinavir, and nelfinavir;
Isoflavonoids: genisteine.
Especially preferred compounds are specified as follows:
1) 3-hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate, 2) 3-acetoxyestra-1,3,5(10)-trien-17(3-yl 3'- sulfamoylphenyl sulfonate, 3) 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 4) 3-hydroxyestra-1,3,5(10)-trien-l7R-y14'-sulfamoylphenyl sulfonate, 5) 2-methoxy-3-hydroxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 6) 3,16a-dihydroxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate, 7) 3,170 -dihydroxyestra-1,3,5(10)-trien-16a-y13'-sulfamoylphenyl sulfonate, 8) 3-benzoyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 9) quinine-3'-sulfamoylphenyl sulfonate, 10) cinchonidine-3'-sulfamoylphenyl sulfonate, 11) zidovudine-3'-sulfamoylphenyl sulfonate, 12) 3-oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 13) 3-oxoandrostan-17P-yl 3'-sulfamoylphenyl sulfonate, 14) 3-oxo-7a-methylandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 15) 3-oxoestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate, and 16) brivudine-3'-sulfamoylphenyl sulfonate.
The therapeutically relevant drug compound is released through hydrolysis from the compounds according to the invention.
In-Vitro Tests:
Carbonic Anhydrase Inhibition Test Principle:
Photometric determination of the inhibition of human carbonic anhydrase I or II with sulfonamides or sulfamates on microtiter plates with the aid of enzymatic conversion of nitrophenyl acetate with a color change from colorless to yellow.
Table 1: IC50 Inhibiting Values of Human Carbonic Anhydrase I
CAII CAI
Inhibitor IC50 (nM) IC50 (nM) Estradiol-3-sulfamat 34 157 10.6 3-Oxoandrost-4-en-17R-yI 120 2300 3'-aminosulfonylphenyl-sulfonat 3-Oxo-7a-methylandrost-4- 120 2300 en-170-yi 3'-aminosulfonyl-hen Isulfonat 3-Hydroxyestra-1,3,5(10)- 81 1700 trien-17p-yl 3'-aminosulfo-n I hen Isulfonat Zidovudinsulfonat 1100 2900 Acetazolamid 61 1200 bekannter CA-Hemmer) 190 Literature: 1) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).
[Key to Table 1:]
Estradiol-3-sulfamat = Estradiol-3-sulfamate 3-Oxoandrost-4-en-17R-yl 3'-aminosulfamoylphenylsulfonat = 3-Oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate 3 -Oxo-7a-methylandrost-4-en-17 0-yl 3'-aminosulfamoylphenylsulfonat = 3 -Oxo-7a-methylandrost-4-en-17(3-yl 3'-aminosulfamoylphenyl sulfonate 3-Hydroxyestra-1,3,5(10)-trien-17(3-yl 3'-aminosulfonylphenylsulfonat = 3-Hydroxyestra-1,3,5(10)-trien-l7R-yl 3'-aminosulfonylphenyl sulfonate Zidovudinsulfonat = Zidovudine Sulfonate Acetazolamid (bekannter CA-Hemmer) = Acetazolamide (Known CA Inhibitor) It was found that the sulfamoyl sulfonate prodrugs according to the invention surprisingly readily inhibit the carbonic anhydrase II. A concentration of the prodrugs, according to the invention, in the erythrocytes can be deduced from this.
Physicochemical Data Solubility in Water a) Kinetic Measurement:
The compounds according to the invention were measured as 10 mmol DMSO
solution in a 0.01 M phosphate buffer solution at pH 7.4 and 25 C with nephelometry and turbidity.
While in a turbid state, the solution to be tested was added drop by drop to the buffer solution until a precipitate settled.
The precipitate was detected in a dilution series (compounds in a phosphate buffer solution according to the invention) by nephelometry.
b.) Thermodynamic Measurement:
The compounds in solid form according to the invention were added to an excess of an aqueous buffer system of various pH values. It was stirred 24 hours at 25 C. After centrifuging, the solution was examined with HPLC (HPLC: column: Xterra MS C18 2.5 m, 30 x 4.6 mm). Two standard gradient systems were used based on the compounds to be measured:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B.
Table 2: Water Solubility Substance Solubility in Water Estradiol-3-sulfamate 0.15 mg/100 ml Testosterone Propionate Insoluble 3-Hydroxyestra-1,3,5(10)-trien-170-y13'- 3 mg/1 sulfamoylphenyl Sulfonate 3-Oxoandrost-4-en-170-yl 3'-sulfamoyl- 5 mg/l phenyl Sulfonate 3-Oxo-7a-methylandrost-4-en-17(3-yl 3'- About 6 mg/1 sulfamoylphenyl Sulfonate The compounds according to the invention show a higher solubility when compared to sulfamate- and carboxylic acid ester prodrugs, which allows for better absorption in the intestine.
Hydrolysis The compounds according to the invention were measured as a DMSO solution in an aqueous buffer of various pH values at 37 C.
The quantification took place through HPLC (HPLC column: Xterra MS C18 2.5 m 4.6 x 30mm). Based on the test substances to be measured, the following gradient system was used for the HPLC:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3=5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B. The quantification took' place after 1 and 2 hours and after 24 hours.
Stability in Simulated Gastric Juice:
Solutions of the compounds according to the invention were incubated at 37 C
in simulated gastric juice (aqueous NaCI solution with pepsin, pH- 1.2).
The quantification took place through HPLC (HPLC-column: Xterra MS C18 2.5 m 4.6 x 30mm) using the gradient system:
A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0.01 % trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B.
The quantification took place after 0.5, 1, 1.5 and 2 hours.
Table 3: Hydrolysis/Stability in Gastric Juice Decomposition in %
pH =1, 37 C pH = 7.4, 37 C
Substance 30 min 1 h 2 h 24 h 1 h 2h. 24 h 3-Hydroxyestra-1,3,5 4 7 14 80 6 13 84 (10)-trien-17(3-yl3'- (pH=1.2) sulfamoyl-phenyl sulfonate 3-Oxoandrost-4-en- 3 6 11 78 6 12 75 17 (3-y13'-sulfamoyl- (pH=1.2) phenyl sulfonate 3-Oxo-7a-methyl- 6 11 71 6 11 70 androst-4-en-17p-yl 3'-sulfamoylphenyl sulfonate 3-Oxoandrost-4-en- 0 0 0 0 0 0 0 17(3-yl n-propionate Carboxylic acid esters are relatively stable in gastric juice (pH - 1) and in the intestine (pH - 7.4), but are cleaved when passing through the intestine by esterases that exist there. During passage through the stomach, however, the stable prodrug remains almost complete.
The cleavage of the carboxylic acid ester thus takes place when passing through the intestine and in the liver.
No enzymes (esterases) are known for sulfonic acid ester. It was therefore surprising that the sulfonates are still cleaved, whereby a simple hydrolysis takes place. Although a slow hydrolysis already takes place in the gastric juice and when the pH = 7.4, the sulfonates have adequate stability to pass through the stomach and the intestine. An esterase cleavage does not take place in the intestine wall. The first-pass effect in the liver is avoided since the sulfonates are bonded with the sulfonamide group to the erythrocytes.
The compounds of general formula (I) according to the invention can, as a function of the meaning of "drug," be used for the treatment and/or prophylaxis of various clinical pictures. For example, the compounds of general formula (I) can be used if the "drug" is a steroid, such as androgen or estrogen, in hormone replacement therapy (HRT) in women and men, or in the treatment of hormonally-induced diseases in men (prostrate cancer, breast cancer, hypogonadism) and in women (endometriosis, breast cancer). In addition, the compounds of general formula (I) according to the invention, in which "drug,"
for example, stands for an androgen or estrogen, can he used for birth control in men and women.
The use of additional active ingredients mentioned for "drug," such as quinine, cinchonidine, hydroxychloroquine, primaquine or mefloquine, relates to the treatment of malaria.
Compounds of general formula (I) according to the invention, in which "drug"
means a cortisol derivative, can be used for the treatment and prophylaxis of inflammatory and/or allergic diseases that are influenced by immunosuppressive agents and/or antiproliferative agents.
Prodrugs according to the invention, in which "drug" means a nucleoside (zidovudine, brivudine, indinavir, nelfinavir), can be used for the treatment of viral diseases (herpes, HIV).
In addition, subjects of the invention are the pharmaceutical compositions that contain the compounds of general formula (I) according to the invention and optionally additional active ingredients, for example gestagens (norethisterone, dienogest, drospirenone, levonorgestrel), antigestagens (mifepristone, onapristone) and/or progesterone receptor modulators (mesoprogestins, such as asoprisnil).
These pharmaceutical compositions and pharmaceutical agents are preferably administered orally. In addition to the usual vehicles and/or diluents, they contain at least one compound of general formula I.
Dosage The prodrugs according to the invention can be administered orally.
Generally, satisfactory results are to be expected both for the treatment and/or prophylaxis of the above-mentioned indications or for birth control if the dosage is carried out in such a way that after the administration of the prodrugs, an amount of the corresponding active ingredient ("drug") is released that corresponds to the highest pharmaceutically used maximum dose of the respective "drug" substance.
The pharmaceutical agents of the invention are produced in a known way with the usual solid or liquid vehicles or diluents and the commonly used pharmaceutical-technical adjuvants corresponding to the desired form of administration with a suitable dosage. The preferred preparations are in a dispensing form that is suitable for oral administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.
Corresponding tablets can be obtained by, for example, mixing the active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxylpolymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tablets can accordingly be produced by coating cores, which are produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the shells for the coated tablets can also consist of several layers, whereby the adjuvants mentioned above with the tablets can be used.
Solutions or suspensions with the compounds of general formula I according to the invention can contain additional taste-improving agents such as saccharin, cyclamate or sugar, as well as, e.g., flavoring substances such as vanilla or orange extract. In addition, they can contain suspending adjuvants such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoate.
The capsules that contain compounds of general formula I can be produced by, for example, the compound(s) of general formula (I) being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.
The prodrugs according to the invention can be synthesized according to the following examples, whereby the latter are used for a more detailed explanation without limiting the invention.
General Synthesis Instructions Variant 1 Reaction with Disulfonic Acid Chlorides A disulfonic acid chloride of general formula S02-X-SO2Cl is dissolved under a cover gas in a base, such as, e.g., pyridine. The corresponding amount of a drug substance is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, the reaction mixture is stirred into a concentrated NH3 solution. The precipitate is filtered off, washed with water and dried. The residue is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel.
Corresponding sulfamoyl sulfonates are obtained.
Variant 2 Reaction with Sulfamoyl Sulfonic Acid Halides A drug substance, as defined above, is dissolved under a cover gas in a base, such as, e.g., pyridine, and an inert solvent, such as, e.g., chloroform. While being cooled, the corresponding amount of a sulfamoyl sulfonic acid halide of general formula SO2Hal is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, water is added, and it is optionally acidified with an acid, such as, e.g., 10%
HCI. It is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant, such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel. Corresponding sulfamoyl sulfonates are obtained.
The corresponding sulfamoyl sulfonic acid halides or disulfonic acid chlorides are commercially available or can be produced by methods that are known to one skilled in the art.
Synthesis Examples Example 1 3 -tert-Butyldimethylsilyloxyestra-1 3 5(10)-trien-17(i-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of 3-tert=butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-ol is added. After 2 hours, the reaction mixture is stirred into 25 ml of a concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-tert-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.14 (s, 6 H, SiMe), 0.77 (s, 3 H, 18-Me), 0.93 (s, 9 H, t.-Bu), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NHZ).
Example 2 3 -Hydroxyestra-1 3 5(10)-trien-l7R-yl 3'-sulfamoylphenyl Sulfonate 300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is dissolved in 20 ml of THF. While being stirred, 200 mg of tetrabutyl ammonium fluoride is added at room temperature. After 1 hour, 20 ml of water is stirred in. The substance is extracted with ethyl acetate. The organic phase is washed with saturated NaCI solution, dried on MgSOa, filtered, concentrated by evaporation and chromatographed on silica gel. 3-Hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-d6): 0.76 (s, 3 H, 18-Me), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NH2), 8.98 (s, 1H, 3-OH).
Example 3 3 -Oxo-7a-methylestra-4-en-17 D-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of MENT is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes; it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-7a-methylestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.66 (d, 3 H, 7-Me), 4.38 (t, 1 H, 17-H), 5.69 (s; 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 4 3-Oxo-androst-4-en-17p-yl 3'-sulfamoylphenyl Sulfonate Variant 1 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine.
Then, 1.0 g of testosterone is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17R-y13'-sulfamoylphenyl sulfonate is obtained.
Variant 2 1.0 g of testosterone is dissolved under argon in 5.5 ml of pyridine. Then, 1.8 g of 3-aminosulfonylphenylsulfonyl chloride is added. After 2 hours, the reaction mixture is stirred into 25 ml of water and acidified with 10% HCI. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
1H-N1VIR (DMSO-D6): 0.78 (s, 3 H, 18-Me), 1.11 (s, 3 H, 19-Me), 4.34 (t, 1 H, H), 5.60 (s, 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 5 Zidovudine-sulfamoylphenyl Sulfonate 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine..
Then, 1.0 g of zidovudine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation and the residue is chromatographically purified on silica gel.
Zidovudine-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-D6): 1.17 (s, 3 H, Me), 2.40 (m, 2 H, CH2), 4.00 (m, 1 H, CH), 4.42 (m, 2 H, CH2), 6.09 (m, 1 H, CH), 7.40 (s, 1 H, CH), 7.66 (s, 2 H, NH2), 7.85-8.30 (3 m + s, 5 H, 4-H), 11.35 (s, 1 H, NH).
Example 6 Cinchonidine-sulfamoylphenyl Sulfonate 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine.
Then, 1.0 g of cinchonidine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation, and the residue is chromatographically purified on silica gel.
Cinchonidine-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 4.99 (m, 2 H, CH=CH2), 5.94 (m, 1 H, CH=CH2), 7.58 (s, 2 H, NH2).
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius, and all parts and percentages are by weight, unless otherwise indicated.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. -
Then, 1.0 g of cinchonidine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation, and the residue is chromatographically purified on silica gel.
Cinchonidine-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 4.99 (m, 2 H, CH=CH2), 5.94 (m, 1 H, CH=CH2), 7.58 (s, 2 H, NH2).
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius, and all parts and percentages are by weight, unless otherwise indicated.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. -
Claims (21)
1. Sulphamoylsulphonate prodrugs of the general formula I
in which X is an optionally substituted C1-C12-alkanediyl group, a C p F2p group where p = 1-5, a mono- or bicyclic, optionally halogen-, hydroxyl- or nitrile-substituted C3-8-cycloalkanediyl group, a mono- to tricyclic, optionally halogen-, hydroxyl-, nitrile- and alkyl-substituted C6-C15-arylene group, a heteroalkanediyl group having 1 to 6 carbon atoms which in place of the carbon contains one or more, identical or different heteroatoms, also a C1-4-alkanediylaryl, a C1-4-alkanediyl-C3-6-cycloalkyl or C3-8-cycloalkanediyl-C1-4-alkyl group, and Drug represents a pharmaceutical active compound which can form a sulphonate group via an OH
group, such as steroids, antimalarial agents, nucleosides, isoflavonoids, which can optionally be substituted.
in which X is an optionally substituted C1-C12-alkanediyl group, a C p F2p group where p = 1-5, a mono- or bicyclic, optionally halogen-, hydroxyl- or nitrile-substituted C3-8-cycloalkanediyl group, a mono- to tricyclic, optionally halogen-, hydroxyl-, nitrile- and alkyl-substituted C6-C15-arylene group, a heteroalkanediyl group having 1 to 6 carbon atoms which in place of the carbon contains one or more, identical or different heteroatoms, also a C1-4-alkanediylaryl, a C1-4-alkanediyl-C3-6-cycloalkyl or C3-8-cycloalkanediyl-C1-4-alkyl group, and Drug represents a pharmaceutical active compound which can form a sulphonate group via an OH
group, such as steroids, antimalarial agents, nucleosides, isoflavonoids, which can optionally be substituted.
2. Sulphamoylsulphonate prodrugs according to Claim 1, wherein Drug represents steroids such as oestrogens, for example oestradiol or oestriol, or androgens, for example testosterone, MENT
(7.alpha.-methyl-19-nor-testosterone), eF-MENT (11-fluoro-7.alpha.-methyl-19-nortestosterone), nandrolone, DHT (dihydro-testosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol, or anti-malarial agents, for example quinine, chinchonidine, hydroxychloroquine, primaquine, mefloquine, or nucleosides consisting of a sugar such as ribose or deoxyribose and of a base such as adenine, guanine, cytosine, thymine or uracil, furthermore zidovudine, brivudine, indinavir, nelfinavir or isoflavonoids, for example genistein.
(7.alpha.-methyl-19-nor-testosterone), eF-MENT (11-fluoro-7.alpha.-methyl-19-nortestosterone), nandrolone, DHT (dihydro-testosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol, or anti-malarial agents, for example quinine, chinchonidine, hydroxychloroquine, primaquine, mefloquine, or nucleosides consisting of a sugar such as ribose or deoxyribose and of a base such as adenine, guanine, cytosine, thymine or uracil, furthermore zidovudine, brivudine, indinavir, nelfinavir or isoflavonoids, for example genistein.
3. Sulphamoylsulphonate prodrugs according to Claim 1, wherein X is an arylene group.
4. Sulphamoylsulphonate prodrugs according to Claim 3, wherein X is an unsubstituted or chlorine-substituted phenylene, pyridylene or thiophenylene radical.
5. Sulphamoylsulphonate prodrugs according to Claim 3 or 4, namely 1) 3-hydroxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate, 2) 3-acetoxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate, 3) 3-tert-butyldimethylsilyloxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate, 4) 3-hydroxyoestra-1,3,5(10)-trien-17.beta.-yl 4'-sulphamoylphenylsulphonate, 5) 2-methoxy-3-hydroxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate,
6) 3,16.alpha.-dihydroxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate,
7) 3,17.beta.-dihydroxyoestra-1,3,5(10)-trien-16.alpha.-yl 3'-sulphamoylphenylsulphonate,
8) 3-benzoyloxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate,
9) quinine-3'-sulphamoylphenylsulphonate,
10)chinchonidine-3'-sulphamoylphenylsulphonate,
11)zidovudine-3'-sulphamoylphenylsulphonate,
12)3-oxoandrost-4-en-17.beta.-yl 3'-sulphamoylphenyl-sulphonate,
13)3-oxoandrostan-17.beta.-yl 3'-sulphamoylphenyl-sulphonate,
14)3-oxo-7.alpha.-methylandrost-4-en-17.beta.-yl 3'-sulph-amoylphenylsulphonate,
15)3-oxooestr-4-en-17.beta.-yl 3'-sulphamoylphenyl-sulphonate,
16)Brivudine-3'-sulphamoylphenylsulphonate.
6. Compounds according to any one of Claims 1, 3 or 4, wherein the active compound is an antimalarial agent such as arteether, artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, chinchonidine, cinchonine, hydroxychloroquine, pamaquine, primaquine, pyrimethamine, quinine or a quinine derivative, such as quinine bisulphate, quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, quinine formate, quinine gluconate, quinine hydroiodide, quinine hydrochloride, quinine salicylate or quinine sulphate.
7. Use of the compounds according to Claim 6 for the prevention of a parasitic attack on erythrocytes.
8. Compounds according to any one of Claims 1-7, wherein the therapeutically desired action takes place by release, in particular hydrolytic cleavage, of the active compound contained in the prodrug or its metabolites.
9. Pharmaceutical composition comprising at least one compound of the general formula I according to any one of Claims 1 to 5 and optionally at least one further active compound together with pharmaceutically tolerable excipients and/or vehicles.
10. Pharmaceutical composition according to Claim 9, wherein the further active compound is a steroidal compound.
11. Pharmaceutical composition according to Claim 10, wherein the further steroidal compound is a gestagen, anti-gestagen or a progesterone receptor modulator.
12. Pharmaceutical composition according to Claim 11, wherein the gestagens contained are norethisterone, dienogest, drospirenone, levo-norgestrel, the anti-gestagens mifepristone, onapristone and progesterone receptor modulators, for example mesoprogestins such as asoprisnil.
13. Use of compounds according to any one of Claims 1 to 8 in the manufacture of a medicament.
14. Use according to Claim 13 in the manufacture of a medicament for hormone replacement therapy.
15. Use of compounds according to Claims 1-8 for female fertility control.
16. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of hormonally caused diseases in men and women.
6. Compounds according to any one of Claims 1, 3 or 4, wherein the active compound is an antimalarial agent such as arteether, artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, chinchonidine, cinchonine, hydroxychloroquine, pamaquine, primaquine, pyrimethamine, quinine or a quinine derivative, such as quinine bisulphate, quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, quinine formate, quinine gluconate, quinine hydroiodide, quinine hydrochloride, quinine salicylate or quinine sulphate.
7. Use of the compounds according to Claim 6 for the prevention of a parasitic attack on erythrocytes.
8. Compounds according to any one of Claims 1-7, wherein the therapeutically desired action takes place by release, in particular hydrolytic cleavage, of the active compound contained in the prodrug or its metabolites.
9. Pharmaceutical composition comprising at least one compound of the general formula I according to any one of Claims 1 to 5 and optionally at least one further active compound together with pharmaceutically tolerable excipients and/or vehicles.
10. Pharmaceutical composition according to Claim 9, wherein the further active compound is a steroidal compound.
11. Pharmaceutical composition according to Claim 10, wherein the further steroidal compound is a gestagen, anti-gestagen or a progesterone receptor modulator.
12. Pharmaceutical composition according to Claim 11, wherein the gestagens contained are norethisterone, dienogest, drospirenone, levo-norgestrel, the anti-gestagens mifepristone, onapristone and progesterone receptor modulators, for example mesoprogestins such as asoprisnil.
13. Use of compounds according to any one of Claims 1 to 8 in the manufacture of a medicament.
14. Use according to Claim 13 in the manufacture of a medicament for hormone replacement therapy.
15. Use of compounds according to Claims 1-8 for female fertility control.
16. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of hormonally caused diseases in men and women.
17. Use according to Claim 13 in the manufacture of a medicament for the therapy and prophylaxis of endometriosis, mammary carcinomas, carcinomas of the prostate or hypogonadism.
18. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of diseases which can be positively influenced by the inhibition of the carboanhydrase activity.
19. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of inflammatory and/or allergic diseases.
20. Process for the preparation of the sulphamoylsulphonate prodrugs of the general formula (I) according to Claim 1 by reaction of an appropriate Drug according to Claims 1 and 2 with a disulphonyl chloride ClSO2-X-SO2Cl in the presence of a base and subsequent treatment with ammonia or by reaction of the appropriate Drug according to Claims 1 and 2 with a sulphamoylsulphonyl halide NH2SO2-X-SO2Cl in the presence of a base.
21. Process according to Claim 20, wherein the base is pyridine.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102005057408.4 | 2005-11-30 | ||
DE102005057408A DE102005057408A1 (en) | 2005-11-30 | 2005-11-30 | New sulfamoylsulfonate prodrugs e.g. useful for protecting red blood cells from attack by parasites or for hormone replacement therapy, female fertility control or treating hormone-associated diseases |
PCT/EP2006/011726 WO2007062874A2 (en) | 2005-11-30 | 2006-11-27 | Sulfamoyl sulfonate prodrugs |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2632272A1 true CA2632272A1 (en) | 2007-06-07 |
Family
ID=37983623
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002632272A Abandoned CA2632272A1 (en) | 2005-11-30 | 2006-11-27 | Sulfamoyl sulfonate prodrugs |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP1957513A2 (en) |
JP (1) | JP2009517424A (en) |
KR (1) | KR20080072956A (en) |
CN (1) | CN101316858A (en) |
AU (1) | AU2006319380A1 (en) |
BR (1) | BRPI0619253A2 (en) |
CA (1) | CA2632272A1 (en) |
CR (1) | CR10003A (en) |
DE (1) | DE102005057408A1 (en) |
EA (1) | EA200801306A1 (en) |
EC (1) | ECSP088489A (en) |
IL (1) | IL191570A0 (en) |
NO (1) | NO20082915L (en) |
WO (1) | WO2007062874A2 (en) |
ZA (1) | ZA200805659B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010110747A1 (en) * | 2009-03-24 | 2010-09-30 | National University Of Singapore | Use of artemisinin derivatives for the treatment of asthma and chronic obstructive pulmonary disease (copd) |
CN101987104A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Ophthalmic composition of heteroaryl sulfamoyl carboxylic ester carbonic anhydrase inhibitor |
CN101987101A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Anti-inflammatory eye composition with glucocorticoid aromatic sulfamoyl sulfonic acid ester as active ingredient |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10027887A1 (en) * | 2000-05-31 | 2001-12-13 | Jenapharm Gmbh | Compounds with a sulfonamide group and pharmaceutical compositions containing these compounds |
DE102004025985A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estriol and estetrol prodrugs |
DE102004025986A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Steroid prodrugs with androgenic effects |
DE102004025966A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estradiol prodrugs |
-
2005
- 2005-11-30 DE DE102005057408A patent/DE102005057408A1/en not_active Ceased
-
2006
- 2006-11-27 EA EA200801306A patent/EA200801306A1/en unknown
- 2006-11-27 EP EP06829354A patent/EP1957513A2/en not_active Withdrawn
- 2006-11-27 CN CNA2006800449086A patent/CN101316858A/en active Pending
- 2006-11-27 CA CA002632272A patent/CA2632272A1/en not_active Abandoned
- 2006-11-27 KR KR1020087015775A patent/KR20080072956A/en not_active Application Discontinuation
- 2006-11-27 BR BRPI0619253-0A patent/BRPI0619253A2/en not_active Application Discontinuation
- 2006-11-27 AU AU2006319380A patent/AU2006319380A1/en not_active Abandoned
- 2006-11-27 WO PCT/EP2006/011726 patent/WO2007062874A2/en active Application Filing
- 2006-11-27 JP JP2008542678A patent/JP2009517424A/en active Pending
-
2008
- 2008-05-20 IL IL191570A patent/IL191570A0/en unknown
- 2008-05-21 CR CR10003A patent/CR10003A/en not_active Application Discontinuation
- 2008-05-30 EC EC2008008489A patent/ECSP088489A/en unknown
- 2008-06-27 NO NO20082915A patent/NO20082915L/en not_active Application Discontinuation
- 2008-06-27 ZA ZA200805659A patent/ZA200805659B/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA200805659B (en) | 2009-10-28 |
EA200801306A1 (en) | 2008-10-30 |
WO2007062874A3 (en) | 2007-07-12 |
KR20080072956A (en) | 2008-08-07 |
WO2007062874B1 (en) | 2007-09-27 |
WO2007062874A2 (en) | 2007-06-07 |
DE102005057408A1 (en) | 2007-05-31 |
CR10003A (en) | 2008-08-21 |
EP1957513A2 (en) | 2008-08-20 |
BRPI0619253A2 (en) | 2011-09-27 |
CN101316858A (en) | 2008-12-03 |
AU2006319380A1 (en) | 2007-06-07 |
IL191570A0 (en) | 2008-12-29 |
JP2009517424A (en) | 2009-04-30 |
NO20082915L (en) | 2008-06-27 |
ECSP088489A (en) | 2008-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6339079B1 (en) | Steroid sulfamates, method for the production and use thereof | |
US20050288267A1 (en) | Estradiol prodrugs | |
AU2021328726A1 (en) | Novel psilocin derivatives having prodrug properties | |
TWI505830B (en) | 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives, method of production thereof and use thereof for the treatment of diseases | |
AU2004289459B2 (en) | Novel 17beta hydroxysteroid dehydrogenase type I inhibitors | |
US8492570B2 (en) | 2-substituted estra-1,3,5(10)-triene-3-yl sulfamate with an anti-tumor action | |
JP2003517436A (en) | 14,15-Cyclopropanosteroids of the 19-norandrostane series, their preparation and pharmaceutical preparations containing said compounds | |
CA2768453A1 (en) | 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-acyloxyalkylene phenyl derivatives, methods for the production thereof and use thereof for treating diseases | |
US20070197488A1 (en) | Prodrugs of ERbeta-selective substances, process for their production, and pharmaceutical compositions that contain these compounds | |
SG174506A1 (en) | Novel amide derivatives of steroidal[3,2-c]pyrazole compounds with glucocorticoid activity | |
US20170349624A1 (en) | Pro-drug forming compounds | |
CA2632272A1 (en) | Sulfamoyl sulfonate prodrugs | |
US20070135375A1 (en) | Sulfamoyl sulfonate prodrugs | |
ES2915058A2 (en) | Process for preparing (15¿lpha,16¿lpha,17¿eta)-estra-1,3,5(10)-triene-3,15,16,17-tetrol (estetrol) and intermediates of said process | |
AU713341B2 (en) | 3-substituted-d-homo-1,3,5,(10)-estratriene derivatives | |
ZA200603613B (en) | Novel 17beta-hydroxysteroid dehydrogenase type I inhibitors | |
US20070135399A1 (en) | Heteroaromatic sulphonamide prodrugs | |
BRPI0619214A2 (en) | heteroaromatic sulfonamide prodrugs | |
ES2312965T3 (en) | SULFAMATES OF D-HOMOESTRA-1,3,5 (10) -TRIEN-3-IL-2-SUBSTITUTED WITH ANTITUMORAL EFFECTS. | |
JPH07215992A (en) | 6-or 7-substituted androsra-1,4-diene derivative | |
MX2008007039A (en) | Heteroaromatic sulfonamide prodrugs | |
US20050131076A1 (en) | Delta15-D-Homosteroids with androgenic action | |
AU2006319382A1 (en) | Prodrugs of ER-beta-selective substances method for production thereof and pharmaceutical compositions comprising the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |